Process for the preparation of substituted anthraquinones and application in the preparation of rheins

ABSTRACT

A process for the preparation of substituted anthraquinones is provided. The anthraquinones can be used to prepare pharmaceutically useful rheins.

This application is a 371 of PCT FR 96/01714 filed Oct. 31, 1996.

The present invention relates to a new process for the preparation ofsubstituted anthraquinones from 1,4-naphthoquinones and to theapplication of the products obtained as intermediates in the synthesisof rheins exhibiting therapeutically useful properties.

The preparation of anthraquinones, such as chrysophanol, by addition of6-methoxy-4-methylpyrone to a naphthoquinone, such as juglone, accordingto the Diels-Alder reaction, has been described by M. E. Jung et al.,J.C.S. Chem. Comm., 95 (1978). However, this process requires a numberof stages, that is to say an addition, followed by an oxidation withsilver oxide, in order to cause aromatization of the rings, and ademethylation. Moreover, the reaction involves the use of diazomethane,which has well-known disadvantages.

Synthetic routes to anthracyclinones by a cyclo-Diels-Alder additionreaction have also been described by M. Petrzilka and J. I. GraysonSynthesis, 753 (1981)!. According to these authors, the regiospecificaddition reaction of a diene with a quinone can be obtained by using aLewis acid composed of the compound BF₃.O(C₂ H₅)₂ as catalyst.

The process according to the present invention makes it possible toprepare substituted anthraquinones from 1,4-naphthoquinones in only twostages and with a satisfactory yield.

The anthraquinones which can be prepared by the process according to thepresent invention can be represented by the general formula (I) below:##STR1## in which R represents a hydrogen atom or a linear or branchedalkyl group containing 1 to 5 carbon atoms, a chloromethyl group, a--COCl group, a --COOR' group or a --CH₂ OR' group where R' is ahydrogen atom or a linear or branched alkyl group containing 1 to 5carbon atoms, R₁ represents a hydrogen atom, a hydroxyl group, a linearor branched alkoxy group containing 1 to 5 carbon atoms or an acyloxygroup containing 1 to 5 carbon atoms, and R₂ represents a hydrogen atomor a linear or branched alkyl group containing 1 to 5 carbon atoms.

In accordance with the process of the invention, a Diels-Alder reactionis carried out between a 1,4-naphthoquinone of general formula (II):##STR2## in which R₁ represents a hydrogen atom, a hydroxyl group, alinear or branched alkoxy group containing 1 to 5 carbon atoms or anacyloxy group containing 1 to 5 carbon atoms and X represents a hydrogenatom or a halogen atom,

and an acyclic diene of formula (III):

    CH.sub.2 ═CR--CH═CH--OR.sub.3                      (III)

in which R represents a hydrogen atom or a linear or branched alkylgroup containing 1 to 5 carbon atoms, a chloromethyl group, a --COClgroup, a --COOR' group or a --CH₂ OR' group where R' is a hydrogen atomor a linear or branched alkyl group containing 1 to 5 carbon atoms andR₃ represents a linear or branched alkyl group containing 1 to 5 carbonatoms or an acyl group in which the alkyl part is linear or branched andcontains 1 to 5 carbon atoms,

and a saponification, aromatization and oxidation reaction issubsequently carried out.

In the above formula (II) representing the starting naphthoquinone, R₁preferably represents a hydroxyl or acetoxy group and X is a hydrogenatom or a chlorine atom. In the general formula (III) representing theacyclic diene, it is preferable for R to represent a hydrogen atom or amethyl group and R₃ a methyl, acetyl or t-butylcarbonyl group.

The acyclic diene of formula (III) used in the reaction described abovecan be a butadiene derivative, such as an ester, and for example1-acetoxy-1,3-butadiene or 1-acetoxy-3-methyl-1,3-butadiene.

Among the naphthoquinones of general formula (II), it is preferable touse juglone, represented by the formula (II) where R₁ represents ahydroxyl group, or 3-chlorojuglone, represented by the same formulawhere X is a chlorine atom. Juglone can be prepared, for example, byoxidation of 1,5-dihydroxynaphthalene in the presence of an appropriatecatalyst, as described in Patent SU-1,817,767, or with chromium oxide,by the method of G. Jesaitis et al., J. Chem. Ed., 49, 436 (1972), oralternatively by oxidation by means of atmospheric oxygen in thepresence of a cobalt-based catalyst, such as salcomine, according to themethod of T. Wakamatsu et al., Synthetic Communications, 14, 1167(1984).

The cyclo-Diels-Alder addition reaction between the 1,4-naphthoquinoneof general formula (II) and the acyclic diene of general formula (III)is preferably carried out in a solvent, which can be chosen fromhydrocarbon solvents and alcohols, such as toluene, xylene, benzene ormethanol, in the presence of acetic anhydride. The acetic anhydride ispreferably used in excess. According to an advantageous embodiment ofthe invention, the reaction is carried out in the presence of acatalytic amount of hydroquinone.

According to an alternative implementational form of the invention, thereaction is carried out in the presence of a Lewis acid which canpreferably be chosen from zinc chloride and ferric chloride.

The addition reaction can be carried out at room temperature or bygently heating at a temperature of between 20 and 60° C. The reactioncan also be carried out by heating at the reflux temperature of thesolvent, for example at a temperature of between 60 and 130° C.approximately, depending on the solvent used.

The process in accordance with the present invention is particularlyadvantageous in that it makes it possible to obtain the anthraquinone,that is to say a compound with an aromatic ring, in a simple way in twostages without it being necessary to isolate intermediate compounds andwithout use of a compound, such as silver oxide, for bringing about thearomatization, in contrast to conventional reaction schemes.

The cycloaddition reaction provides the tetrahydroanthraquinonescorresponding to the anthraquinones of formula (I) in the form of amixture of two isomers, where the R group is in the 2 or 3 position andthe OR₃ group is in the 4 or 1 position respectively, in variableproportions depending on the operating conditions. Thesetetrahydroanthraquinones can be easily converted into anthraquinones offormula (I) by saponification, oxidation and aromatization, for exampleby treatment with an oxidant such as N-bromo-succinimide or manganesedioxide. According to an advantageous embodiment, thesaponification-oxidation-aromatization reaction is carried out directlyon the mixture of the isomeric tetrahydroanthraquinones, which makes itpossible to facilitate the treatment and to improve the overall yield.

The substituted anthraquinones obtained by the process according to thepresent invention can be used in the preparation of rheins of generalformula (IV) ##STR3## in which R₅ represents an acetyl group and R₆represents a --CO₂ R' group where R' is a hydrogen atom or a linear orbranched alkyl group containing 1 to 5 carbon atoms, which are obtainedby carrying out an acetylation of the substituted anthraquinones ofgeneral formula (I), followed, if necessary, by an oxidation and by apurification.

These rheins are useful in human and veterinary therapeutics as activeprinciples of medicaments, in particular as nonsteroidalanti-inflammatories in the treatment of arthritis and of osteoarthritis.

The following examples illustrate the invention in more detail withoutlimiting the scope thereof.

EXAMPLE 1

A mixture of 0.5 g of juglone, 0.93 g of1-acetoxy-3-methyl-1,3-butadiene and 0.9 ml of acetic anhydride in 10 mlof toluene is brought to reflux (approximately 110° C.) in a 100 mlround-bottomed flask and is maintained at reflux for 48 hours, in thepresence of a catalytic amount of hydroquinone.

The progress of the reaction is monitored by thin layer chromatography.The reaction is complete when the juglone is no longer detected.

The toluene is removed by distillation under reduced pressure and thecrude product obtained is chromatographed on a column of silica gel,elution being carried out with a cyclohexane/ethyl ether (80/20)mixture.

180 mg of mixture are thus obtained, which mixture is composed of 65% of1-acetoxy-3-methyl-1,1a,4,4a-tetrahydroanthranone and 35% of4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydro-anthraquinone.

The two isomers are rapidly saponified in basic medium (dilute sodiumcarbonate) and oxidized and aromatized using 150 mg of manganese(IV)dioxide. The two isomers are separated by chromatography on a column ofsilica gel. The chrysophanol thus obtained with a yield of 9% isidentified by its NMR spectrum.

EXAMPLE 2

The preparation is carried out as in Example 1 but by using 5.4 ml ofacetic anhydride in the toluene and by heating at reflux for 24 hours.

The reaction is complete after approximately 24 hours. The toluene isremoved by distillation under reduced pressure.

200 mg of mixture are thus obtained, which mixture is composed of 65% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 35%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetra-hydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 10%.

EXAMPLE 3

The preparation is carried out as in Example 2 but by replacing thetoluene with xylene.

The reaction takes place in the same way and 200 mg of mixture areobtained, which mixture is composed of 65% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 35%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 10%.

EXAMPLE 4

A mixture of 0.5 g of juglone, 0.93 g of1-acetoxy-3-methyl-1,3-butadiene and 195 mg of zinc chloride in 10 ml oftoluene is brought to reflux in a 100 ml round-bottomed flask. Themixture is maintained at reflux for approximately 90 minutes, in thepresence of a catalytic amount of hydroquinone.

The juglone is no longer detected by thin layer chromatography after 90minutes.

The toluene is removed by distillation under reduced pressure and thecrude product obtained is chromatographed on a column of silica gel,elution being carried out with a cyclohexane/ethyl ether (80/20)mixture.

210 mg of mixture are thus obtained, which mixture is composed of 70% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 30%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 11%.

EXAMPLE 5

0.5 g of juglone and 0.93 g of 1-acetoxy-3-methyl-1,3-butadiene aremixed in 10 ml of toluene in a 100 ml round-bottomed flask. The mixtureis maintained at room temperature with stirring for approximately 14hours, in the presence of a catalytic amount of hydroquinone.

The juglone is no longer detected by thin layer chromatography after 14hours.

The toluene is removed by distillation under reduced pressure and thecrude product obtained is chromatographed on a column of silica gel,elution being carried out with a cyclohexane/ethyl ether (80/20)mixture.

670 mg of mixture are thus obtained, which mixture is composed of 80% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 20%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 42%.

EXAMPLE 6

The reaction is carried out as in Example 4, by using 78 mg of zincchloride but by allowing the reaction to take place at room temperature,with stirring, in the presence of a catalytic amount of hydroquinone.

Monitoring by thin layer chromatography shows that the juglone hasreacted after 14 hours.

The desired product is collected after distilling off the toluene underreduced pressure and chromatography on a column of silica gel, elutionbeing carried out with a cyclohexane/ethyl ether (80/20) mixture.

700 mg of mixture are thus obtained, which mixture is composed of 70% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 30%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 38%.

EXAMPLE 7

The preparation is carried out as in Example 6, but by replacing thezinc chloride with 93 mg of ferric chloride in 10 ml of toluene, at roomtemperature with stirring.

The starting juglone is no longer detected by thin layer chromatographyafter 14 hours.

After distilling off the toluene under reduced pressure, the crudeproduct is chromatographed on a column of silica gel, elution beingcarried out with a cyclohexane/ethyl ether (80/20) mixture. 710 mg ofmixture are thus obtained, which mixture is composed of 55% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone sic! and45% of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetra-hydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 30%.

EXAMPLE 8

The preparation is carried out as in Example 5 by reacting a mixture of0.6 g of 3-chlorojuglone and 0.93 g of 1-acetoxy-3-methyl-1,3-butadienein 10 ml of toluene.

The juglone is no longer detected by thin layer chromatography after 14hours, which shows that the reaction is complete.

The toluene is removed by distillation under reduced pressure and thecrude product obtained is chromatographed on a column of silica gel,elution being carried out with a cyclohexane/ethyl ether (80/20)mixture.

660 mg of mixture are thus obtained, which mixture is composed of 90% of1-acetoxy-8-hydroxy-3-methyl-1,1a,4,4a-tetrahydroanthraquinone and 10%of 4-acetoxy-8-hydroxy-2-methyl-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, chrysophanol is obtained with a yieldof 46%.

EXAMPLE 9

The preparation is carried out as in Example 5 by reacting a mixture of0.5 g of juglone and 0.83 g of 1-acetoxy-1,3-butadiene in 10 ml oftoluene.

The juglone is no longer detected by thin layer chromatography after 12hours.

The toluene is removed by distillation under reduced pressure and thecrude product obtained is chromatographed on a column of silica gel,elution being carried out with a cyclohexane/ethyl ether (80/20)mixture. 660 mg of mixture are thus obtained, which mixture is composedof 80% of 1-acetoxy-8-hydroxy-1,1a,4,4a-tetrahydroanthraquinone and 20%of 4-acetoxy-8-hydroxy-1,1a,4,4a-tetrahydroanthraquinone.

After saponification, oxidation and aromatization according to thetechnique described in Example 1, 1,8-dihydroxyanthraquinone is obtainedwith a yield of 41%.

We claim:
 1. A process for the preparation of substituted anthraquinonesrepresented by the general formula (I) below ##STR4## in which Rrepresents a hydrogen atom or a linear or branched alkyl groupcontaining 1 to 5 carbon atoms, a chloromethyl group, a --COCl group, a--COOR' group or a --CH₂ OR' group where R' is a hydrogen atom or alinear or branched alkyl group containing 1 to 5 carbon atoms, R₁represents a hydrogen atom, a hydroxyl group, a linear or branchedalkoxy group containing 1 to 5 carbon atoms or an acyloxy groupcontaining 1 to 5 carbon atoms, and R₂ represents a hydrogen atom or alinear or branched alkyl group containing 1 to 5 carbon atoms,comprisingcarrying out a Diels-Alder reaction between a 1,4-naphthoquinone ofgeneral formula (II): ##STR5## in which R₁ represents a hydrogen atom, ahydroxyl group, a linear or branched alkoxy group containing 1 to 5carbon atoms or an acyloxy group containing 1 to 5 carbon atoms and Xrepresents a hydrogen atom or a halogen atom, and an acyclic diene offormula (III):

    CH.sub.2 ═CR--CH═CH--OR.sub.3                      (III)

in which R represents a hydrogen atom or a linear or branched alkylgroup containing 1 to 5 carbon atoms, a chloromethyl group, a --COClgroup, a --COOR' group or a --CH₂ OR' group where R' is a hydrogen atomor a linear or branched alkyl group containing 1 to 5 carbon atoms andR₃ represents an acetyl group, in the presence of a catalytic amount ofhydroquinone, followed by a saponification, aromatization, and oxidationreaction, in order to obtain the substituted anthraquinone of generalformula (I).
 2. A process according to claim 1, wherein the reaction iscarried out in the presence of acetic anhydride.
 3. A process accordingto claim 1, wherein the reaction is carried out in the presence of aLewis acid.
 4. A process according to claim 3, wherein the Lewis acid ischosen from zinc chloride and ferric chloride.
 5. A process according toclaim 1, wherein R₁ represents a hydroxyl or acetoxy group and X is ahydrogen atom or a chlorine atom.
 6. A process according to claim 1,wherein R represents a hydrogen atom or a methyl group.
 7. A processaccording to claim 6, wherein the diene of formula (III) is chosen from1-acetoxy-1,3-butadiene or 1-acetoxy-3-methyl-1,3 butadiene.
 8. A methodfor preparation of a rhein of general formula (IV) ##STR6## in which R₅represents an acetyl group and R₆ represents a --CO₂ R' group where R'is a hydrogen atom or a linear or branched alkyl group containing 1 to 5carbon atoms, wherein an acetylation of the substituted anthraquinone offormula (I) according to claim 1 is carried out, followed, optionally,by an oxidation.
 9. A process according to claim 1, wherein the reactionis carried out at room temperature.
 10. A process according to claim 1,which has only two stages.
 11. A process according to claim 1, whereinthe 1,4-naphthoquinone is juglone or 3-chlorojuglone.
 12. A processaccording to claim 1, wherein the reaction is carried out in thepresence of an alcohol or hydrocarbon solvent.
 13. A process accordingto claim 1, wherein the substituted anthraquinone compriseschrysophanol.